Ubiquitin signaling in the NF-κB pathway

IkB ubiquitination, IKK and IkB ubiquitin ligase

NF-κB is a transcription factor that regulates a plethora of genes in response to diverse stimuli. Aberrant regulation of NF-κB has been linked to many human diseases, such as cancer and autoimmune diseases. NF-κB is normally sequestered in the cytoplasm by proteins of the IkB family. Upon stimulation, distinct signaling cascades converge on the IkB kinase complex (IKK), which phosphorylates IkBs and targets these inhibitors for degradation by the ubiquitin proteasome pathway. NF-κB then enters the nucleus to turn on downstream target genes.

Ubiquitin-mediated activation of TAK1 and IKK

Recently, we have focused on how IKK is regulated by different pathways. Interestingly, we found that ubiquitination activates IKK through a proteasome-independent mechanism. We found that TRAF6, an essential protein for NF-κB activation by interleukin-1b and Toll-like receptors (TLRs), is a ubiquitin E3 ligase that functions together with an E2 complex, Ubc13/Uev1A, to synthesize polyubiquitin chains linked through lysine 63 (K63) of ubiquitin. These ubiquitin chains bind to the TAB2 and TAB3 subunits of the TAK1 kinase complex, resulting in TAK1 kinase activation. TAK1 then phosphorylates and activates IKK. Recent research in our lab and others have supported a critical role of ‘non-degradative’ ubiquitination in the activation of TAK1 and IKK in different pathways, including those triggered by TNF receptor, T cell receptor, RIG-I like receptor, NOD-like receptors and DNA damage.